The present invention relates to a cross-linked hydrogel composition that is flowable when heated to above its melting point and an elastic solid at physiological body temperature and below. The present invention is also directed to the use of such hydrogels as a biomaterial to repair or supplement body tissue and, in particular, an intervertebral disc nucleous.
Hydrogels are water-swellable or water-swollen materials whose structure is typically defined by a crosslinked or interpenetrating network of hydrophilic homopolymers or copolymers. The hydrophilic homopolymers or copolymers can be water-soluble in free form, but in a hydrogel they may be rendered insoluble generally due to the presence of covalent, ionic, or physical crosslinks. In the case of physical crosslinking, the linkages can take the form of entanglements, crystallites, or hydrogen-bonded structures. The crosslinks in a hydrogel provide structure and physical integrity to the polymeric network.
Poly(vinyl alcohol) (“PVA”) hydrogels have been used for biomedical applications, including nucleus pulposus and soft tissue replacements or repair. For example, U.S. Pat. No. 5,047,055 discloses the use of 100% semi-crystalline PVA for nucleus pulposus replacement. Another PVA hydrogel for nucleus replacement is disclosed in U.S. Pat. No. 7,214,245, which describes the addition of poly(vinyl pyrrolidone) (“PVP”) to the PVA hydrogel for stabilization. The addition of PVP was found to reduce PVA degradation in the body, which is the result of melting out of smaller crystallites over time. This degradation can reduce the hydrogel's mechanical properties in addition to leaching molecules into the surrounding physiological environment. International Publication Number WO 2009/146331 A1 discloses an injectable nucleus pulposus replacement consisting of PVA/PVP and PEG. This hydrogel consists of physical cross-links, which do not offer advantages such as stability or property tailoring that is typical of chemical cross-linking.
Chemical cross-linking of PVA can help achieve the desired mechanical and swelling properties, in addition to further reducing the degradation of PVA due to the use of covalent bonds giving network structure. A chemically cross-linked network is not as susceptible to the melting out of the crystallites, as is a physically cross-linked network. U.S. Pat. No. 5,941,909 discloses the use of PVA chemically cross-linked with glutaraldehyde for filling material for soft tissue implant prostheses and implants. U.S. patent application Ser. No. 12/747,411 describes the use of cross-linking polyethyleneimine with a hydrogen-bonding polymer such as PVA. These hydrogel networks have to be injected immediately after mixing, which is an added complication for the surgeon performing the nucleus pulposus replacement. Another chemically cross-linked PVA hydrogel, used for human vitreous substitutes, PVA is cross-linked with trisodium trimetaphosphate. This cross-linked material has a modulus of 3.9 to 1290 Pa, which is sufficient for human vitreous substitutes but is too low for nucleus pulposus replacement and other soft tissues. PVA has also been cross-linked with glycidyl methacrylate with the use of a photoinitiator 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone for nucleus replacement. The cross-linked nucleus replacement is not an injectable material. Another chemically cross-linked material is an injectable cross-linked scaffold for nucleus pulposus regeneration. This scaffold is composed of atelocollagen type II, hyaluronan, aggrecan and crosslinked with mTGase (see, e.g., Halloran, D. O., et al., An injectable cross-linked scaffold for nucleus pulposus regeneration. Biomaterials, 2008. 29: p. 438-447). It is a significant drawback, however, that this scaffold is not suitable for total nucleus replacement because it has a low modulus (250-1300 Pa).
Accordingly, there is a need in the art for a cross-linked hydrogel that is injectable and does not suffer from the aforementioned drawbacks.